NEOPLASIA2
Factors that influence the incidence of cancer: Incidence may be related to
Genetic polymorphism:
Individual predisposition to disease
Individual response to environmental agents
Individual response to drugs (P450)
Ethnic Factors
Geographic & environment & other factors (Multifactorial)
Prostatic & Colorectal & Breast CA: High in USA
Gastric CA: High in Japan
Skin CA: High in New Zealand
Hepatocellular CA: High in Africa & China
Nasopharyngeal CA: Far East
Burkitt Lymphoma: Africa
Environment: ""جدول عن اخر موضوع بالصفحة الثانية
Diet: ↑ consumption of fibers + ↓ fat in diet → ↓risk of developing colorectal cancer
Obesity/Overweight:
Accumulation of some hormones (estrogen in fats)
unopposed estrogen (++) → cancers (breast & endometrium)
Occupation:
Sunlight: Associated with skin CAs (SCC, BCC, melanoma) & More commonly in fair-skin people
Personal habits:
Smoking: lung & nasopharyngeal CA.
Alcohol: Alcoholic hepatitis, liver cirrhosis
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Age:
In general, cancer incidence ≈ AGE n However, certain cancers occur more in children:
Acute Leukemia & Some Lymphomas
Some CNS Tumors & Blastomas
Bone & soft tissue Sarcomas
Heredity (5% of cancers are familial):
AD:
CDKN2A: melanoma
APC gene: Familial Adenomatous Polyposis Coli
MEN1 & RET genes: Multiple endocrine neoplasia (MEN syndromes)
NF1 & NF2 genes: Neurofibromatosis 1&2
BRCA 1 &2: breast & ovarian cancers
RB gene: Retinoblastoma
MSH2, MLH1, MSH6: Hereditary non-polyposis colon cancer
PTCH1: Nevoid basal cell carcinoma
TP53: Li-Fraumeni Syndrome
AR syndromes of Defective DNA Repair: neurofibromas & some skin
pigmentations (Café au lait spots).
Chromosomal & DNA instability
Example:
Nucleotide excision repair genes:
XERODERMA PIGMENTOSUM (BEST EXAMPLE)
ATM: Ataxia telangiectasia
BLM: Bloom syndrome
Genes involved in REPIR of DNA cross links: Fanconi anemia
Familial cancers with no specific phenotype & multifactorial:
Family members have higher incidence to common cancers: COLON & BREAST & OVARY CA
Younger age groups, multiple or bilateral, two or more family members are affected.
Some linked to inheritance of mutant genes (BRCA-1 & BRCA-2) (AD)
Acquired Predisposing Conditions:
Precursor lesions:
Squamous metaplasia/dysplasia of bronchial epithelium & lung squamous cell Ca.
Endometrial Hyperplasia & Ca.
Leukoplakia (Dysplasia) of the cervix, vulva, penis or oral cavity & associated SCC.
Villous Adenoma (benign in glandular epithelium of colon) & Colorectal Ca
Immunodeficiency states: virus-related CA (HPV → cervical dysplasia & SCC)
Chronic inflammation
Inflammatory bowel diseases: Colorectal CA & Pancreatitis: pancreatic CA
Gastritis: gastric adenocarcinoma & MALT lymphoma & Chronic cervicitis: cervical CA
Hepatitis: hepatocellular CA
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CARCINOGENESIS: MOLECULAR BASIS OF CANCER
Intro:
Neoplasms arising from a single clone of cells: MONOCLONAL proliferation
CLONE:
A Cell, Cell product that is genetically identical to the unit from which it was derived.
A population of identical units, cells, or individuals that derive from the same ancestral line.
Principles:
Tumors arise from clonal growth of transformed cells that have developed mutations in
several classes of genes:
Growth promoting proto-oncogenes
Growth inhibiting tumor suppressor genes (Regular suppressor (RB) & Guardians (TP53))
Genes regulating apoptosis
Genes involved in DNA repair
More than one mutation in above result in abnormal growth of cells
Genetic Lesions in Tumors:
Different Gene Lesions:
Point mutation: Change in a single base in a nucleotide sequence
may activate an oncogene, or inactivate a tumor suppressor gene (TP53)
RAS oncogene (codon 12, 13) in Pancreatic carcinoma & subset of colorectal carcinoma
Translocation:
A gene rearrangement /movement of genetic materials (from one chromosome to another)
seen in some solid tumors: Ewing Sarcoma t.(11;22) (q24;q12)
mainly in lymphoid & hematopoietic tumors:
Burkitt Lymphoma: 8;14
Follicular B Cell Lymphoma: 14;18
Chronic myeloid leukemia (CML): 9;22 (PHILADELPHIA Chromosome)
Fusion Gene is produced: BCR-ABL (tyrosine kinase activity)
Gene amplification:
Double minutes: Small fragments of extrachromosomal DNA
Homogenous staining regions produced by chromosomal segments with various lengths
&uniform staining intensity
Examples:
Neuroblastoma: N-MYC
Breast carcinoma: HER2/Neu (important for targeted Ab therapy)
Chromosomal deletions:
More commonly seen in non-hematopoietic & solid tumors
EX: Retinoblastoma RB gene 13q14, TP53 gene 17q also several in colorectal CA
Chromosomes loss or gain: Change from the normal multiples of 23 (Aneuploidy)
There are two types of mutations:
Driver mutations:
Alter the function of CA genes
directly contribute CA development
and those that do not are termed passenger mutations (acquired mutations)
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Micro RNAs:
Non-coding Single stranded RNA of about 22 nucleotides act as regulators of genes
Overexpression of miRNAs → ↓ the expression of tumor suppressors → carcinogenesis
Deletion or loss of expression of miRNAs → overexpression of proto-oncogenes.
Epigenetic changes: Reversible, heritable changes that occur without mutation
Through methylation → may silence tumor suppressor genes & repair genes → carcinogenesis
Carcinogenesis is a MULTISTEP PROCESS
Accumulation of mutations of different genes that may come from different gene groups.
Ex: adenoma → carcinoma sequence in the colon:
FIRST HIT: NL mucosa undergoes a mutation (activation mutation in one allele of APC gene)
2nd HIT:
Inactivation mutation: in another allele of the same gene
Other gene abnormalities: in other genes (B-catenin), which makes the mucosa at risk
Activation mutation in oncogenes: K-RAS → mucosa at greater risk of transforming
Inactivation mutation of p53 → formation of adenoma
further mutations → Low-grade → High-grade dysplasia in adenoma
further mutations (telomerase) & gross chromosomal alterations → carcinoma
transformation of nevi → melanoma.
Usually benign don’t transform → malignant neoplasms, but this rule has some exceptions
Tumor Progression:
Stepwise accumulation of mutations resulting in ↑ features of malignancy:
More aggressive & Less responsive to therapy
Heterogeneous Cancer: tumor cells develop mutations different that the other groups in the same
tumor (differences between cancer cells within a single tumor)
Hallmarks of Cancer:
Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals
Evasion of apoptosis Altered cellular metabolism
Limitless replicative potential (Immortality) Evasion of immune surveillance
Ability to invade & metastasize Sustained angiogenesis
Deregulating cellular energetics Tumor promoting Inflammation
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GENES IN NEOPLASTIC TRANSFORMATION:
Genes coding for growth: Classified by site of action
Proto-oncogenes: NL. /Oncogenes: Mutant/overexpressed proto-oncogenes → Oncoproteins
They include genes coding:
GFs Cell surface receptors
Cell cycle proteins Signal transduction proteins
Inhibitors of apoptosis Nuclear transcription factors
Oncogenes coding Growth Factors:
Cell growth is stimulated by its own GF (autocrine) or other cell (paracrine -from stromal cells)
Platelet derived growth factor (PDGF) seen in glioblastomas
Transforming Growth Factor (TGF-a) in sarcomas
Products of other oncogenes (RAS) may cause overexpression of GF
Oncogenes coding Growth Factor Receptors:
GF integrates with membrane receptor that have tyrosine kinase (TK) activity → nucleus
Mutant receptor → continuous signals even in the absence of GF
Normal but overexpressed → hypersensitive to GF
Epidermal GF receptor family:
ERBB1 in 80% of squamous cell carcinoma of the lung & 50% of GBM
ERBB2 (HER 2 NEU) in 20% of breast CA, less in adenocarcinomas of lung, ovary,
stomach, and salivary glands
Increase = POOR PROGNOSIS, presence of these Rs help in giving immune-targeted
therapy (breast CA: treating the HER 2 NEU if it was in the tumor cells)
Oncogenes in signal transduction:
RAS action: RAS oncogene
Commonest oncogene mutation
present in over 30% of CAs (pancreas & Colon)
Point mutations in codon 12, 13 are present
Active (+) RAS → Signal transduction (RAF/MAP-K or
PI3-K/AKT pathways) → transcription activation
+ RAS (GTP) -- GTPase activity by (GAP) →Inactive (GDP)
Mutations in GAPs (NF1): Neurofibromatosis 1
Action of ABL:
Non-receptor associated TK signal transmission
NL ABL is located in nucleus (promotes apoptosis)
CML: 9;22 translocation →BCR-ABL hybrid gene
This new gene protein is retained in the cytoplasm
where it has tyrosine kinase activity
activates all of the signals downstream of RAS → cell proliferation
New action is Proliferation + No Apoptosis
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Nuclear Transcription Factors:
DNA transcription regulated by genes :MYC*, JUN, FOS
In normal: MYC protein + DNA → Activation of Cyclin Dependent Kinases (CDKs)
Initiation of cell cycle → ↓ MYC
MYC mutation → sustained activation
Examples:
Dysregulation of MYC in Burkitt lymphoma due to translocation t (8;14)
MYC amp. in Breast, colon, lung CA.
NMYC amp. in neuroblastoma
Cyclins & Cyclin Dependant – Kinases regulate cell cycle phases
Family of proteins that control entry of the cells at specific phases of cell cycle (D, E, A, B)
Level of a specific cyclin ↑ at a specific phase & ↓ rapidly after the cell departs that phase
Function by phosphorylating certain proteins (RB protein)
Cyclins bind to CDKs, activating them
Two important checkpoints:
Cyclin D family → CDK4 & CDK6 at G1 → S phase
Cyclin B-CDK1 activate G2 → M transition
Activity of CDK/ Cyclin is regulated by CDK inhibitors (Selective or nonselective inhibition)
Examples: p21, p27 & p57 inhibit all CDKs
INK4 Inhibitors (p15, p16, p18 & p19) inhibit CDK4 & CDK6
Expression of p21 is controlled by the tumor suppressor protein p53 → G1 phase arrest
Mutations that dysregulate activity of cyclins & CDKs → cell proliferation
Cyclin D is overexpressed in breast, liver & esophageal cancers
Amplification of CDK4 gene is present in melanomas, sarcomas & glioblastoma
Disabling mutations of CDKN2A (encoding p16): germline (melanoma-prone kindreds)
or acquired (pancreas /esophagus Ca, GBM)
Cancer Suppressor Genes:
Growth inhibitory pathway by:
Regulate cell cycle: RB gene
Regulate cycle & apoptosis: TP53
Block GF signals: TGF-b
APC regulates b-catenin
Cancer suppressor genes are recessive genes which may be lost in familial or sporadic cases.
In cases with familial predisposition for development of tumors, affected persons inherit:
one defective (nonfunctional) copy of a tumor suppressor gene
lose the second one through somatic mutation.
In sporadic cases, both copies are lost through somatic mutations.
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RB gene (Governor of cell cycle):
First studied in Retinoblastoma (RB gene → RB protein)
Both copies of gene must be lost for neoplastic transformation to occur (loss of heterozygosity)
Familial (RB → RB) or Sporadic (RB → RB → RB)
Mode of action of RB gene:
G1→ S requires the activity of cyclin E/CDK2
Cyclin E is dependent on the E2F family of transcription factors (TFs)
Active hypophosphorylated RB binds to & inhibits the E2F→ no transcription of cyclin E
GF signaling leads to cyclin D expression & activation of cyclin D-CDK4/6 complexes
phosphorylate RB, inactivating the protein & releasing E2F → TRANSCRIPTION (G1 → S)
Many oncogenic DNA viruses (HPV) encode proteins (E7) → bind to RB & render it non-functional
Retinoblastoma:
Sporadic in 60% of cases, Familial (40%)
In familial form, patients carry one mutation → followed by 2nd mutation in retinal cells
No tumor develops unless two alleles in chr. 13q14 become mutant (two hit theory)
Familial form: ↑ incidence of bilateral (osteosarcoma & other tumors)
TP53 (Guardian of Genome):
The most commonly mutated gene (and suppressor gene) in human CA
homozygous loss in 70% of CA
TP53 is a negative regulator of cell cycle (protein product is p53)
(Guardian/Policeman): preventing genetically damaged cells from progressing through new cycle.
p53 is inactivated by its negative regulator MDM2.
DNA damage / other stresses will lead to the dissociation of the p53 and MDM2 complex.
Mode of activation & action:
p53 senses DNA damage /other stresses through sensors: protein kinases
(Ataxia telangiectasia mutated (ATM) protein)
p53 released from MDM2 & activated with longer half-life
Transcription of CDKI gene CDKN1A (p21) → cell cycle arrest at G1 (Quiescence)
Result: more time for repair → Normal
If repair fails:
Senescence (permanent cell cycle arrest)
Apoptosis
Fixed mutation = NEOPLASIA
More functions of TP53:
Transcription of certain repair genes, micro RNAs (inhibit cyclins and BCL2)
positive regulator of apoptosis (BAX & PUMA).
Significance of TP53 mutation:
Acquired mutation in many cancers (colon, breast, lung, leukemia)
Inherited mutation in one allele: Li-Fraumeni syndrome → 25 fold ↑ malignancy:
sarcoma, leukemia, breast carcinoma and gliomas
May be blocked by some DNA viruses (oncogenic HPV, HBV, EBV & others) producing
viral-induced cancers
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